DESCRIPTION: This is a proposal to determine and study the three- dimensional structure of the A1 domain of human von Willebrand (vWF) factor. The A1 domain is responsible for binding the platelet glycoprotein GPlb receptor complex and thereby activating platelet aggregation. Binding to native vWF only occurs under high shear conditions or when the factor is absorbed to surfaces, but the isolated At domain binds GPlb in the solution phase. Certain heritable forms of von Willebrand's disease map as single substitution mutations within the A1 domain. Thus, the structure of this domain will shed light on a number of important biological and pathological functions of this molecule.